Puzzling role of genetic risk factors in human longevity: "risk alleles" as pro-longevity variants.

Abstract

Complex diseases are major contributors to human mortality in old age. Paradoxically, many genetic variants that have been associated with increased risks of such diseases are found in genomes of long-lived people, and do not seem to compromise longevity. Here we argue that trade-off-like and conditional effects of genes can play central role in this phenomenon and in determining longevity. Such effects may occur as result of: (i) antagonistic influence of gene on the development of different health disorders; (ii) change in the effect of gene on vulnerability to death with age (especially, from "bad" to "good"); (iii) gene-gene interaction; and (iv) gene-environment interaction, among other factors. A review of current knowledge provides many examples of genetic factors that may increase the risk of one disease but reduce chances of developing another serious health condition, or improve survival from it. Factors that may increase risk of a major disease but attenuate manifestation of physical senescence are also discussed. Overall, available evidence suggests that the influence of a genetic variant on longevity may be negative, neutral or positive, depending on a delicate balance of the detrimental and beneficial effects of such variant on multiple health and aging related traits. This balance may change with age, internal and external environments, and depend on genetic surrounding. We conclude that trade-off-like and conditional genetic effects are very common and may result in situations when a disease "risk allele" can also be a pro-longevity variant, depending on context. We emphasize importance of considering such effects in both aging research and disease prevention.

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Citation

Published Version (Please cite this version)

10.1007/s10522-015-9600-1

Publication Info

Ukraintseva, Svetlana, Anatoliy Yashin, Konstantin Arbeev, Alexander Kulminski, Igor Akushevich, Deqing Wu, Gaurang Joshi, Kenneth C Land, et al. (2016). Puzzling role of genetic risk factors in human longevity: "risk alleles" as pro-longevity variants. Biogerontology, 17(1). pp. 109–127. 10.1007/s10522-015-9600-1 Retrieved from https://hdl.handle.net/10161/14816.

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Scholars@Duke

Ukraintseva

Svetlana Ukraintseva

Research Professor in the Social Science Research Institute

Dr. Ukraintseva studies causes of human aging and related decline in resilience, to identify genetic and other factors responsible for the increase in mortality risk with age eventually limiting longevity. She explores complex relationships, including trade-offs, between physiological aging-changes and risks of major diseases (with emphasis on Alzheimer’s and cancer), as well as survival, to find new genetic and other targets for anti-aging interventions and disease prevention. She also investigates possibilities of repurposing of existing vaccines and treatments for AD prevention and interventions into the aging. For this, Dr. Ukraintseva and her team use data from several large human studies containing rich genetic and phenotypic information (including longitudinal measurements) on thousands of individuals. Dr. Ukraintseva is a PI and Key Investigator on several NIH funded grants, and has more than 130 peer-reviewed publications, including in major journals such as Nature Reviews, Stroke, European Journal of Human Genetics, and some other.

Yashin

Anatoli I. Yashin

Research Professor in the Social Science Research Institute
Arbeev

Konstantin Arbeev

Associate Research Professor in the Social Science Research Institute

Konstantin G. Arbeev received the M.S. degree in Applied Mathematics from Moscow State University (branch in Ulyanovsk, Russia) in 1995 and the Ph.D. degree in Mathematics and Physics (specialization in Theoretical Foundations of Mathematical Modeling, Numerical Methods and Programming) from Ulyanovsk State University (Russia) in 1999. He was a post-doctoral fellow in Max Planck Institute for Demographic Research in Rostock (Germany) before moving to Duke University in 2004 to work as a Research Scientist and a Senior Research Scientist in the Department of Sociology and the Social Science Research Institute (SSRI).  He is currently an Associate Research Professor in SSRI. Dr. Arbeev's major research interests are related to three interconnected fields of biodemography, biostatistics and genetic epidemiology as pertains to research on aging. The focus of his research is on discovering genetic and non-genetic factors that can affect the process of aging and determine longevity and healthy lifespan. He is interested in both methodological advances in this research area as well as their practical applications to analyses of large-scale longitudinal studies with phenotypic, genetic and, recently, genomic information. Dr. Arbeev authored and co-authored more than 150 peer-reviewed publications in these areas.

Kulminski

Alexander Kulminski

Research Professor in the Social Science Research Institute

Igor Akushevich

Research Professor in the Social Science Research Institute
Wu

Dequing Wu

Research Scientist, Senior
Land

Kenneth C. Land

John Franklin Crowell Distinguished Professor Emeritus of Sociology

I received my Ph.D. in sociology and mathematics from the University of Texas at Austin in 1969. After a year of postdoctoral study in mathematical statistics at Columbia University in New York City, I taught there and was a member of the staff of the Russell Sage Foundation for three years. I then was successively a member of the faculties of the University of Illinois at Urbana Champaign and the University of Texas at Austin before joining the Duke Sociology Department as Chairman in 1986. I served as Chair of Sociology from January 1986 to August 1997. My main research interests are contemporary social trends and quality-of-life measurement, social problems, demography, criminology, organizations, and mathematical and statistical models and methods for the study of social and demographic processes. I have done extensive research in each of these areas and have been elected a Fellow of the American Statistical Association (1978), the Sociological Research Association (1981), the American Association for the Advancement of Science (1992), the International Society for Quality-of-Life Studies (1997), and the American Society of Criminology (2004). I teach Contemporary Social Problems (SOCIOL 111), Advanced Methods of Demographic Analysis, and the Demography of Aging Proseminar (SOCIOL 750S). My other interests include tennis, jogging (10 kilometers), and music.


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